Is CHFR p.Ser232Leu (c.695C>T) pathogenic?

CHFR p.Ser232Leu (c.695C>T) is classified Likely benign in CHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.0501); Rare (popmax 0.346%, mid).

How common is CHFR p.Ser232Leu (c.695C>T) in the general population?

CHFR p.Ser232Leu (c.695C>T) is rare (popmax 0.346%, mid) (gnomAD).

What do computational predictors say about CHFR p.Ser232Leu (c.695C>T)?

AlphaMissense predicts likely benign (score 0.0501) — an in-silico prediction, not a clinical call.

CHFR p.Ser232Leu

c.695C>T · VCV4228038

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0501 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.346%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0501	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.072	GERP -2.8
Regional constraint	o/e 0.99	unconstrained · MANE · 34 kb · p 0.86 · regional, not allelic
Overall
CADD	5.887	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 S244L vs ClinVar S232L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.346% Middle Eastern · 21/6,062 alleles

Filtering AF 0.232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.0216% 349/1,614,196 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.346%	289
Admixed American	0.14%	715
Remaining individualsnot grpmax-eligible	0.0656%	1,525
European (non-Finnish)	0.0163%	6,146
African / African-American	0.012%	8,340
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,882

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.Ser232Leu
Coding: c.695C>T
MANE Select: NM_001161346
Type: single nucleotide variant
Location: chr12:132861523 (GRCh38)
Gene constraint: LOEUF 0.929 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.22 · 6 PDB
Residue 232: the 'disordered' region

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-ser232leu (accessed [today's date]).

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