Is EXPH5 p.Val899Ala (c.2696T>C) pathogenic?

EXPH5 p.Val899Ala (c.2696T>C) is classified Benign in EXPH5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0981); Common (popmax 9.95%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about EXPH5 p.Val899Ala (c.2696T>C)?

AlphaMissense predicts likely benign (score 0.0981) — an in-silico prediction, not a clinical call.

EXPH5 p.Val899Ala

Q: How common is EXPH5 p.Val899Ala (c.2696T>C) in the general population?

EXPH5 p.Val899Ala (c.2696T>C) is common (popmax 9.95%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2696T>C · rs17108112 · VCV1532812

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0981 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.95%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0981	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -6.36	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 -0.8	GERP -3.6
Regional constraint	o/e 0.99	unconstrained · MANE · 84 kb · p 0.73 · regional, not allelic
Overall
CADD	0.077	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 9.95% African / African-American · 7,468/75,038 alleles

Filtering AF 9.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.69%

Overall 0.632% 10,197/1,614,166 alleles · common exomes 5,903/1,461,850 · genomes 4,294/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.95%	10
Middle Eastern	1.83%	55
Admixed American	1.25%	80
Remaining individualsnot grpmax-eligible	0.91%	110
Ashkenazi Jewishnot grpmax-eligible	0.209%	477
Amishnot grpmax-eligible	0.11%	912
European (non-Finnish)	0.101%	987
Finnishnot grpmax-eligible	0.039%	2,562
South Asian	0.0165%	6,073

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.Val899Ala
Coding: c.2696T>C
MANE Select: NM_015065
dbSNP: rs17108112
Type: single nucleotide variant
Location: chr11:108512811 (GRCh38)
Gene constraint: LOEUF 1.142 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 36.39
Residue 899: a UniProt-annotated variant site (in); the 'disordered' region

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

Similar variants

EXPH5 p.Ala1429Ser Uncertain significance ★★ ⚠ same type
EXPH5 p.Arg1727Lys Uncertain significance ★★ ⚠ same type
EXPH5 p.Asn1548Asp Uncertain significance ★★ ⚠ same type
EXPH5 p.Asp741His Uncertain significance ★★ ⚠ same type
EXPH5 p.Gln1464Arg Uncertain significance ★★ ⚠ same type
EXPH5 p.Gly54Arg Uncertain significance ★★ ⚠ same type
EXPH5 p.Leu1519Arg Uncertain significance ★★ ⚠ same type
EXPH5 p.Leu234Phe Uncertain significance ★★ ⚠ same type

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-val899ala (accessed [today's date]).

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