Is CRLF3 p.Ser270Cys (c.809C>G) pathogenic?

CRLF3 p.Ser270Cys (c.809C>G) is classified Uncertain significance in CRLF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.1906); Ultra-rare (popmax 0.0549%, nfe).

How common is CRLF3 p.Ser270Cys (c.809C>G) in the general population?

CRLF3 p.Ser270Cys (c.809C>G) is ultra-rare (popmax 0.0549%, nfe) (gnomAD).

What do computational predictors say about CRLF3 p.Ser270Cys (c.809C>G)?

AlphaMissense predicts likely benign (score 0.1906) — an in-silico prediction, not a clinical call.

CRLF3 p.Ser270Cys

c.809C>G · rs368649092 · VCV3077531

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1906 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0549%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1906	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 40 kb · p 0.056 · regional, not allelic
Overall
CADD	31.0	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 0.0549% European (non-Finnish) · 648/1,179,902 alleles

Filtering AF 0.0513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.0415% 669/1,613,806 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0549%	1,821
Remaining individualsnot grpmax-eligible	0.0192%	5,206
Finnishnot grpmax-eligible	0.00937%	10,667
African / African-American	0.00401%	24,964

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: CRLF3
Protein: p.Ser270Cys
Coding: c.809C>G
MANE Select: NM_015986
dbSNP: rs368649092
Type: single nucleotide variant
Location: chr17:30793467 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.15
Residue 270: the fibronectin type-iii domain

Full CRLF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRLF3 p.Ala308Ser Uncertain significance ★ ⚠ same type
CRLF3 p.Ala308Thr Uncertain significance ★ ⚠ same type
CRLF3 p.Arg348Gln Uncertain significance ★ ⚠ same type
CRLF3 p.Arg38Cys Uncertain significance ★ ⚠ same type
CRLF3 p.Asn394Ser Uncertain significance ★ ⚠ same type
CRLF3 p.Asn60Lys Uncertain significance ★ ⚠ same type
CRLF3 p.Asp225Gly Uncertain significance ★ ⚠ same type
CRLF3 p.Asp240Glu 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/crlf3-p-ser270cys (accessed [today's date]).

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