Is GSAP p.Val141Phe (c.421G>T) pathogenic?

GSAP p.Val141Phe (c.421G>T) is classified Uncertain significance in GSAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely pathogenic (0.7705); Very rare (popmax 0.005%, amr).

How common is GSAP p.Val141Phe (c.421G>T) in the general population?

GSAP p.Val141Phe (c.421G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about GSAP p.Val141Phe (c.421G>T)?

AlphaMissense predicts likely pathogenic (score 0.7705) — an in-silico prediction, not a clinical call.

GSAP p.Val141Phe

c.421G>T · VCV4032708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7705	likely pathogenic · top 8% in GSAP
REVEL	0.218	benign-leaning
SaProt	LLR -10.35	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 105 kb · p 0.86 · regional, not allelic
Overall
CADD	26.4	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 0.005% Admixed American · 3/59,964 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000187% 3/1,602,576 alleles · very rare exomes 3/1,450,300 · genomes 0/152,276 · joint denominator

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: GSAP
Protein: p.Val141Phe
Coding: c.421G>T
MANE Select: NM_017439
Type: single nucleotide variant
Location: chr7:77387395 (GRCh38)
Gene constraint: LOEUF 1.2 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.78

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

Similar variants

GSAP p.Pro756Thr Benign ★★ same type
GSAP p.Ala185Val Uncertain significance ★ ⚠ same type
GSAP p.Ala429Thr Uncertain significance ★ ⚠ same type
GSAP p.Ala433Thr Uncertain significance ★ ⚠ same type
GSAP p.Ala457Asp Uncertain significance ★ ⚠ same type
GSAP p.Ala510Ser Uncertain significance ★ ⚠ same type
GSAP p.Ala510Thr Uncertain significance ★ ⚠ same type
GSAP p.Ala7Thr 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/gsap-p-val141phe (accessed [today's date]).

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