Is CD1C p.Ser22Phe (c.65C>T) pathogenic?

CD1C p.Ser22Phe (c.65C>T) is classified Uncertain significance in CD1C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0924); Ultra-rare (popmax 0.0145%, nfe).

How common is CD1C p.Ser22Phe (c.65C>T) in the general population?

CD1C p.Ser22Phe (c.65C>T) is ultra-rare (popmax 0.0145%, nfe) (gnomAD).

What do computational predictors say about CD1C p.Ser22Phe (c.65C>T)?

AlphaMissense predicts likely benign (score 0.0924) — an in-silico prediction, not a clinical call.

CD1C p.Ser22Phe

c.65C>T · rs139113876 · VCV2522979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0924 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0145%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0924	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -4.7	GERP -3.1
Regional constraint	o/e 1.06	unconstrained · MANE · 3,408 bp · p 0.27 · regional, not allelic
Overall
CADD	0.186	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 0.0145% European (non-Finnish) · 171/1,178,812 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.011% 178/1,611,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0145%	6,894
Remaining individualsnot grpmax-eligible	0.00801%	12,488
Admixed American	0.00167%	59,894
African / African-American	0.00134%	74,614

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: CD1C
Protein: p.Ser22Phe
Coding: c.65C>T
MANE Select: NM_001764 · reported on NM_001765
dbSNP: rs139113876
Type: single nucleotide variant
Location: chr1:158291137 (GRCh38)

Full CD1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/cd1c-p-ser22phe (accessed [today's date]).

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