Is AMACR p.Val304Phe (c.910G>T) pathogenic?

AMACR p.Val304Phe (c.910G>T) is classified Uncertain significance in AMACR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-11). AlphaMissense: likely benign (0.1479); Ultra-rare (popmax 0.0133%, afr); Associated with AMACR-related disorder.

What condition is associated with AMACR p.Val304Phe (c.910G>T)?

AMACR p.Val304Phe (c.910G>T) is associated with AMACR-related disorder (ClinVar).

How common is AMACR p.Val304Phe (c.910G>T) in the general population?

AMACR p.Val304Phe (c.910G>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about AMACR p.Val304Phe (c.910G>T)?

AlphaMissense predicts likely benign (score 0.1479) — an in-silico prediction, not a clinical call.

AMACR p.Val304Phe

c.910G>T · rs762820381 · VCV2632046

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1479 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AMACR-related disorder

Computational evidence

Protein change
AlphaMissense	0.1479	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -8.05	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 -6.6	GERP -4.3
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.71 · regional, not allelic
Overall
CADD	0.254	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 0.0133% African / African-American · 10/74,922 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000682% 11/1,614,054 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,492
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: AMACR
Protein: p.Val304Phe
Coding: c.910G>T
MANE Select: NM_014324
dbSNP: rs762820381
Type: single nucleotide variant
Location: chr5:33989332 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.79

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

Disease context

AMACR-related disorder

Similar variants

AMACR p.Ser52Pro Pathogenic/Likely pathogenic ★★ same condition
AMACR p.Pro296Leu Uncertain significance ★★ ⚠ same condition
AMACR p.Gly83Ser Likely pathogenic ★ same condition
AMACR p.Asp123Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
AMACR p.Arg40Gly Uncertain significance ⚠ same condition
AMACR p.Arg97Gln Uncertain significance ⚠ same condition
AMACR p.Ile353Leu Uncertain significance ⚠ same condition
AMACR p.Phe300Ser 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/amacr-p-val304phe (accessed [today's date]).

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