Is EXPH5 p.Pro548Ser (c.1642C>T) pathogenic?

EXPH5 p.Pro548Ser (c.1642C>T) is classified Uncertain significance in EXPH5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-10). AlphaMissense: likely benign (0.1139); Ultra-rare (popmax 0.0294%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXPH5 p.Pro548Ser (c.1642C>T)?

EXPH5 p.Pro548Ser (c.1642C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXPH5 p.Pro548Ser (c.1642C>T) in the general population?

EXPH5 p.Pro548Ser (c.1642C>T) is ultra-rare (popmax 0.0294%, nfe) (gnomAD).

What do computational predictors say about EXPH5 p.Pro548Ser (c.1642C>T)?

AlphaMissense predicts likely benign (score 0.1139) — an in-silico prediction, not a clinical call.

EXPH5 p.Pro548Ser

c.1642C>T · rs139699634 · VCV1499923

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1139	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -4.84	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 1.4	GERP -3, phastCons 0.81
Regional constraint	o/e 0.99	unconstrained · MANE · 84 kb · p 0.73 · regional, not allelic
Overall
CADD	10.73	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0294% European (non-Finnish) · 347/1,178,974 alleles

Filtering AF 0.0268% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.0235% 379/1,611,440 alleles · ultra-rare exomes 338/1,459,218 · genomes 41/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0294%	3,398
Finnishnot grpmax-eligible	0.025%	3,992
Remaining individualsnot grpmax-eligible	0.0176%	5,672
African / African-American	0.00267%	37,404
South Asian	0.00221%	45,207
Admixed American	0.00167%	59,712

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.Pro548Ser
Coding: c.1642C>T
MANE Select: NM_015065
dbSNP: rs139699634
Type: single nucleotide variant
Location: chr11:108513865 (GRCh38)
Gene constraint: LOEUF 1.142 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 36.39

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXPH5 p.Ala1429Ser Uncertain significance ★★ ⚠ same condition
EXPH5 p.Arg1727Lys Uncertain significance ★★ ⚠ same condition
EXPH5 p.Asn1548Asp Uncertain significance ★★ ⚠ same condition
EXPH5 p.Asp741His Uncertain significance ★★ ⚠ same condition
EXPH5 p.Gln1464Arg Uncertain significance ★★ ⚠ same condition
EXPH5 p.Gly54Arg Uncertain significance ★★ ⚠ same condition
EXPH5 p.Leu1519Arg Uncertain significance ★★ ⚠ same condition
EXPH5 p.Leu234Phe 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-pro548ser (accessed [today's date]).

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