Is EXPH5 p.Pro394Ser (c.1180C>T) pathogenic?

EXPH5 p.Pro394Ser (c.1180C>T) is classified Uncertain significance in EXPH5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.2676); Very rare (popmax 0.00983%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXPH5 p.Pro394Ser (c.1180C>T)?

EXPH5 p.Pro394Ser (c.1180C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXPH5 p.Pro394Ser (c.1180C>T) in the general population?

EXPH5 p.Pro394Ser (c.1180C>T) is very rare (popmax 0.00983%, nfe) (gnomAD).

What do computational predictors say about EXPH5 p.Pro394Ser (c.1180C>T)?

AlphaMissense predicts likely benign (score 0.2676) — an in-silico prediction, not a clinical call.

EXPH5 p.Pro394Ser

c.1180C>T · rs757312754 · VCV2595616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00983%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2676	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -5.56	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 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 84 kb · p 0.73 · regional, not allelic
Overall
CADD	24.8	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 0.00983% European (non-Finnish) · 116/1,179,614 alleles

Filtering AF 0.00834% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00777%

Overall 0.0075% 121/1,613,202 alleles · very rare exomes 116/1,461,050 · genomes 5/152,152 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00983%	10,169
Admixed American	0.00334%	29,980
Remaining individualsnot grpmax-eligible	0.0032%	31,230
African / African-American	0.00134%	74,886

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.Pro394Ser
Coding: c.1180C>T
MANE Select: NM_015065
dbSNP: rs757312754
Type: single nucleotide variant
Location: chr11:108514327 (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-pro394ser (accessed [today's date]).

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