Is F2R p.Val154Ala (c.461T>C) pathogenic?

F2R p.Val154Ala (c.461T>C) is classified Uncertain significance in F2R (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely benign (0.1502); Ultra-rare (popmax 0.0373%, sas).

How common is F2R p.Val154Ala (c.461T>C) in the general population?

F2R p.Val154Ala (c.461T>C) is ultra-rare (popmax 0.0373%, sas) (gnomAD).

What do computational predictors say about F2R p.Val154Ala (c.461T>C)?

AlphaMissense predicts likely benign (score 0.1502) — an in-silico prediction, not a clinical call.

F2R p.Val154Ala

c.461T>C · VCV3511250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1502 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1502	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -1.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 17 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	22.2	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 0.0373% South Asian · 34/91,086 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.00619% 100/1,614,240 alleles · ultra-rare exomes 97/1,461,894 · genomes 3/152,346 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0373%	2,679
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00508%	19,667
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Admixed American	0.00333%	30,011

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: F2R
Protein: p.Val154Ala
Coding: c.461T>C
MANE Select: NM_001992
Type: single nucleotide variant
Location: chr5:76732686 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.50 · 13 PDB

Full F2R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F2R p.Leu38= Benign ★★ same type
F2R p.Ser172= Benign ★★ same type
F2R p.Tyr381Cys Benign ★★ same type
F2R p.Val246= Benign ★★ same type
F2R p.Ala10Val Uncertain significance ★ ⚠ same type
F2R p.Ala203Thr Uncertain significance ★ ⚠ same type
F2R p.Ala268Ser Uncertain significance ★ ⚠ same type
F2R p.Arg214Ser 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/f2r-p-val154ala (accessed [today's date]).

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