Is CLVS2 p.His241Asn (c.721C>A) pathogenic?

CLVS2 p.His241Asn (c.721C>A) is classified Uncertain significance in CLVS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.1133); Very rare (popmax 0.00949%, nfe).

How common is CLVS2 p.His241Asn (c.721C>A) in the general population?

CLVS2 p.His241Asn (c.721C>A) is very rare (popmax 0.00949%, nfe) (gnomAD).

What do computational predictors say about CLVS2 p.His241Asn (c.721C>A)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

CLVS2 p.His241Asn

c.721C>A · rs751775763 · VCV2207760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00949%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -5.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 58 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	22.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00949% European (non-Finnish) · 112/1,179,980 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.00706% 114/1,613,972 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00949%	10,536
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: CLVS2
Protein: p.His241Asn
Coding: c.721C>A
MANE Select: NM_001010852
dbSNP: rs751775763
Type: single nucleotide variant
Location: chr6:123055851 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.15
Residue 241: the cral-trio domain

Full CLVS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLVS2 p.Ala139Gly Uncertain significance ★ ⚠ same type
CLVS2 p.Ala146Thr Uncertain significance ★ ⚠ same type
CLVS2 p.Arg138Gly Uncertain significance ★ ⚠ same type
CLVS2 p.Arg215Trp Uncertain significance ★ ⚠ same type
CLVS2 p.Arg48Cys Uncertain significance ★ ⚠ same type
CLVS2 p.Asp272Gly Uncertain significance ★ ⚠ same type
CLVS2 p.Glu19Gln Uncertain significance ★ ⚠ same type
CLVS2 p.Glu316Gly 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/clvs2-p-his241asn (accessed [today's date]).

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