Is FGFR1 p.Ala74Val (c.221C>T) pathogenic?

FGFR1 p.Ala74Val (c.221C>T) is classified Benign in FGFR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0732); Very rare (popmax 0.00941%, nfe); Associated with Pfeiffer syndrome.

What condition is associated with FGFR1 p.Ala74Val (c.221C>T)?

FGFR1 p.Ala74Val (c.221C>T) is associated with Pfeiffer syndrome, hypogonadotropic hypogonadism 2 with or without anosmia (ClinVar).

How common is FGFR1 p.Ala74Val (c.221C>T) in the general population?

FGFR1 p.Ala74Val (c.221C>T) is very rare (popmax 0.00941%, nfe) (gnomAD).

What do computational predictors say about FGFR1 p.Ala74Val (c.221C>T)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

FGFR1 p.Ala74Val

c.221C>T · rs143241978 · VCV2930457

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00941%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Pfeiffer syndrome

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -5.80	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 -0.35	GERP -4.7
Regional constraint	o/e 1.03	unconstrained · MANE · 29 kb · p 0.67 · regional, not allelic
Overall
CADD	9.841	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 0.00941% European (non-Finnish) · 111/1,179,922 alleles

Filtering AF 0.00791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00744%

Overall 0.00731% 118/1,613,648 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00941%	10,630
Admixed American	0.00334%	29,980
Remaining individualsnot grpmax-eligible	0.0032%	31,225
African / African-American	0.00267%	37,456
South Asian	0.0011%	90,984

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: FGFR1
Protein: p.Ala74Val
Coding: c.221C>T
MANE Select: NM_023110
dbSNP: rs143241978
Type: single nucleotide variant
Location: chr8:38429819 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 74: a disulfide bond; the ig-like c2-type 1 domain

Full FGFR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Pfeiffer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypogonadotropic hypogonadism 2 with or without anosmia

Similar variants

FGFR1 p.Ala74= Likely benign ★ same residue
FGFR1 c.1977+1G>A Pathogenic/Likely pathogenic ★★ same condition
FGFR1 c.1977+1G>T Pathogenic/Likely pathogenic ★★ same condition
FGFR1 c.448+1G>A Likely pathogenic ★★ same condition
FGFR1 c.449-6G>A Likely pathogenic ★★ same condition
FGFR1 c.91+1G>A Pathogenic/Likely pathogenic ★★ same condition
FGFR1 p.Arg209Cys Likely pathogenic ★★ same condition
FGFR1 p.Arg250Gln Pathogenic ★★ 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/fgfr1-p-ala74val (accessed [today's date]).

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