Is CHFR p.Leu346Val (c.1036C>G) pathogenic?

CHFR p.Leu346Val (c.1036C>G) is classified Uncertain significance in CHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-16). AlphaMissense: likely pathogenic (0.5795); Very rare (popmax 0.00169%, nfe).

How common is CHFR p.Leu346Val (c.1036C>G) in the general population?

CHFR p.Leu346Val (c.1036C>G) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about CHFR p.Leu346Val (c.1036C>G)?

AlphaMissense predicts likely pathogenic (score 0.5795) — an in-silico prediction, not a clinical call.

CHFR p.Leu346Val

c.1036C>G · rs1255988921 · VCV2546614

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5795	likely pathogenic
REVEL	0.258	benign-leaning
SaProt	LLR -6.51	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 9.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 34 kb · p 0.86 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L358V vs ClinVar L346V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% European (non-Finnish) · 20/1,180,042 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0013% 21/1,614,116 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00169%	59,002
African / African-American	0.00133%	74,948

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.Leu346Val
Coding: c.1036C>G
MANE Select: NM_001161346
dbSNP: rs1255988921
Type: single nucleotide variant
Location: chr12:132857435 (GRCh38)
Gene constraint: LOEUF 0.929 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.22 · 6 PDB

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

Similar variants

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.Ala499Val 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-leu346val (accessed [today's date]).

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