Is FFAR4 p.Arg99Ser (c.295C>A) pathogenic?

FFAR4 p.Arg99Ser (c.295C>A) is classified Uncertain significance in FFAR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-02). AlphaMissense: likely pathogenic (0.9747); Very rare (popmax 0.00458%, nfe).

How common is FFAR4 p.Arg99Ser (c.295C>A) in the general population?

FFAR4 p.Arg99Ser (c.295C>A) is very rare (popmax 0.00458%, nfe) (gnomAD).

What do computational predictors say about FFAR4 p.Arg99Ser (c.295C>A)?

AlphaMissense predicts likely pathogenic (score 0.9747) — an in-silico prediction, not a clinical call.

FFAR4 p.Arg99Ser

c.295C>A · VCV3850012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9747	likely pathogenic · top 2% in FFAR4
REVEL	0.246	benign-leaning
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 6.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 21 kb · p 0.89 · regional, not allelic
Overall
CADD	27.2	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 0.00458% European (non-Finnish) · 54/1,179,860 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00347% 56/1,611,694 alleles · very rare exomes 54/1,459,490 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,849
Remaining individualsnot grpmax-eligible	0.0016%	62,454
African / African-American	0.00133%	74,928

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: FFAR4
Protein: p.Arg99Ser
Coding: c.295C>A
MANE Select: NM_001195755
Type: single nucleotide variant
Location: chr10:93567015 (GRCh38)
Gene constraint: LOEUF 1.035 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 16 PDB
Residue 99: an α-helix

Full FFAR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RBP4 p.Gly93Asp Likely pathogenic ★★ same type
FFAR4 c.696+2944C>T Uncertain significance ★ same type
FFAR4 c.696+2949C>T Uncertain significance ★ same type
FFAR4 c.696+2974T>C Uncertain significance ★ same type
FFAR4 p.Ala131Val Uncertain significance ★ ⚠ same type
FFAR4 p.Ala160Ser Uncertain significance ★ ⚠ same type
FFAR4 p.Ala167Val Uncertain significance ★ ⚠ same type
FFAR4 p.Ala315Thr 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/ffar4-p-arg99ser (accessed [today's date]).

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