Is EXPH5 p.Gly1663Arg (c.4987G>A) pathogenic?

EXPH5 p.Gly1663Arg (c.4987G>A) is classified Benign in EXPH5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.115); Common (popmax 64.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive.

What do computational predictors say about EXPH5 p.Gly1663Arg (c.4987G>A)?

AlphaMissense predicts likely benign (score 0.115) — an in-silico prediction, not a clinical call.

EXPH5 p.Gly1663Arg

Q: What condition is associated with EXPH5 p.Gly1663Arg (c.4987G>A)?

EXPH5 p.Gly1663Arg (c.4987G>A) is associated with epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive (ClinVar).

Q: How common is EXPH5 p.Gly1663Arg (c.4987G>A) in the general population?

EXPH5 p.Gly1663Arg (c.4987G>A) is common (popmax 64.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Epidermolysis bullosa simplex due to exophilin 5 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.4987G>A · rs2640779 · VCV1227267

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.115 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 64.8%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.115	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP 1
Regional constraint	o/e 0.99	unconstrained · MANE · 84 kb · p 0.73 · regional, not allelic
Overall
CADD	10.64	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 64.8% East Asian · 29,061/44,862 alleles

Filtering AF 64.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 63.9%

Overall 25.7% 415,040/1,613,818 alleles · common exomes 381,328/1,461,750 · genomes 33,712/152,068 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	64.8%	2
Admixed American	42.6%	2
Finnishnot grpmax-eligible	31.9%	3
Ashkenazi Jewishnot grpmax-eligible	30.2%	3
South Asian	27.1%	4
Remaining individualsnot grpmax-eligible	26.5%	4
European (non-Finnish)	24.1%	4
Amishnot grpmax-eligible	18.3%	5
Middle Eastern	16.3%	6
African / African-American	5.55%	18

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EXPH5
Protein: p.Gly1663Arg
Coding: c.4987G>A
MANE Select: NM_015065
dbSNP: rs2640779
Type: single nucleotide variant
Location: chr11:108510520 (GRCh38)
Gene constraint: LOEUF 1.142 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 36.39
Residue 1663: the 'disordered' region; a UniProt-annotated variant site (in)

Full EXPH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Epidermolysis bullosa simplex due to exophilin 5 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

EXPH5 p.Arg19Gly Benign ★★ same condition
EXPH5 p.Ser676Asn Benign ★★ same condition
EXPH5 p.Thr1974= Benign ★★ same condition
EXPH5 p.Leu215Ter Likely pathogenic ★ same condition
EXPH5 p.Arg1808Ter Conflicting classifications of pathogenicity ★ same condition
EXPH5 p.Arg842Lys Uncertain significance ★ ⚠ same condition
EXPH5 p.Cys1639Ter Conflicting classifications of pathogenicity ★ same condition
EXPH5 p.His964Tyr Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/exph5-p-gly1663arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown