Is EXPH5 p.Val525Phe (c.1573G>T) pathogenic?

EXPH5 p.Val525Phe (c.1573G>T) is classified Benign/Likely benign in EXPH5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-16). AlphaMissense: likely benign (0.1446); Low-frequency (popmax 3.87%, nfe).

How common is EXPH5 p.Val525Phe (c.1573G>T) in the general population?

EXPH5 p.Val525Phe (c.1573G>T) is low-frequency (popmax 3.87%, nfe) (gnomAD).

What do computational predictors say about EXPH5 p.Val525Phe (c.1573G>T)?

AlphaMissense predicts likely benign (score 0.1446) — an in-silico prediction, not a clinical call.

EXPH5 p.Val525Phe

c.1573G>T · rs12146448 · VCV1599077

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1446 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.87%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1446	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.12	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 -0.11	GERP -1.7
Regional constraint	o/e 0.99	unconstrained · MANE · 84 kb · p 0.73 · regional, not allelic
Overall
CADD	10.84	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 3.87% European (non-Finnish) · 45,587/1,177,456 alleles

Filtering AF 3.84% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.83%

Overall 3.39% 54,563/1,607,610 alleles · low-frequency exomes 50,884/1,455,362 · genomes 3,679/152,248 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	3.87%	26
Remaining individualsnot grpmax-eligible	3.5%	29
Ashkenazi Jewishnot grpmax-eligible	2.97%	34
Middle Eastern	2.58%	39
Amishnot grpmax-eligible	2.53%	40
South Asian	2.45%	41
Finnishnot grpmax-eligible	2.2%	46
Admixed American	2.15%	46
East Asian	0.916%	109
African / African-American	0.648%	154

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.Val525Phe
Coding: c.1573G>T
MANE Select: NM_015065
dbSNP: rs12146448
Type: single nucleotide variant
Location: chr11:108513934 (GRCh38)
Gene constraint: LOEUF 1.142 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 36.39
Residue 525: a UniProt-annotated variant site (in)

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-val525phe (accessed [today's date]).

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