Is CHFR p.Ala499Val (c.1496C>T) pathogenic?

CHFR p.Ala499Val (c.1496C>T) is classified Uncertain significance in CHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.0917); Ultra-rare (popmax 0.034%, nfe).

How common is CHFR p.Ala499Val (c.1496C>T) in the general population?

CHFR p.Ala499Val (c.1496C>T) is ultra-rare (popmax 0.034%, nfe) (gnomAD).

What do computational predictors say about CHFR p.Ala499Val (c.1496C>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

CHFR p.Ala499Val

c.1496C>T · rs201350082 · VCV2361748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -7.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 0.78, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 12 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	20.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A511V vs ClinVar A499V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.034% European (non-Finnish) · 395/1,163,418 alleles

Filtering AF 0.0311% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.03%

Overall 0.0267% 422/1,581,038 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.034%	2,945
Remaining individualsnot grpmax-eligible	0.0261%	3,827
Admixed American	0.00722%	13,844
African / African-American	0.00673%	14,856
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,988
South Asian	0.00116%	86,148

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: CHFR
Protein: p.Ala499Val
Coding: c.1496C>T
MANE Select: NM_001161346
dbSNP: rs201350082
Type: single nucleotide variant
Location: chr12:132848721 (GRCh38)
Gene constraint: LOEUF 0.929 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.22 · 6 PDB
Residue 499: an α-helix

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

Similar variants

CHFR p.Ala499= Benign ★ same residue
CHFR p.Leu472= Benign ★★ same type
CHFR p.Gln411Ter Likely pathogenic ★ same type
CHFR p.Ala279Val Uncertain significance ★ ⚠ same type
CHFR p.Ala280Ser Uncertain significance ★ ⚠ same type
CHFR p.Ala569Val Uncertain significance ★ ⚠ same type
CHFR p.Arg21His Uncertain significance ★ ⚠ same type
CHFR p.Arg266Gly 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/chfr-p-ala499val (accessed [today's date]).

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