Is CD44 p.Ser516Leu (c.1547C>T) pathogenic?

CD44 p.Ser516Leu (c.1547C>T) is classified Uncertain significance in CD44 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1125); Very rare (popmax 0.00354%, sas).

How common is CD44 p.Ser516Leu (c.1547C>T) in the general population?

CD44 p.Ser516Leu (c.1547C>T) is very rare (popmax 0.00354%, sas) (gnomAD).

What do computational predictors say about CD44 p.Ser516Leu (c.1547C>T)?

AlphaMissense predicts likely benign (score 0.1125) — an in-silico prediction, not a clinical call.

CD44 p.Ser516Leu

c.1547C>T · rs572774966 · VCV2475479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00354%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1125	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -7.27	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 2.3	GERP -1.9, phastCons 0.85
Regional constraint	o/e 1.07	unconstrained · MANE · 32 kb · p 0.099 · regional, not allelic
Overall
CADD	19.99	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 0.00354% South Asian · 3/84,646 alleles

Filtering AF 0.000941% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000461%

Overall 0.00019% 3/1,575,882 alleles · very rare

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: CD44
Protein: p.Ser516Leu
Coding: c.1547C>T
MANE Select: NM_000610
dbSNP: rs572774966
Type: single nucleotide variant
Location: chr11:35209995 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.31 · 7 PDB
Residue 516: the 'stem' region; the 'disordered' region

Full CD44 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD44 c.367+7T>C Benign ★★ same type
CD44 p.Arg463Gln Benign ★★ same type
CD44 p.Arg673Gln Likely benign ★★ ⚠ same type
CD44 p.Gly462= Benign ★★ same type
CD44 p.Ile457Val Benign ★★ same type
CD44 p.Phe245= Benign ★★ same type
CD44 p.Thr163= Benign ★★ same type
CD44 p.Thr393Met Benign ★★ ⚠ 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/cd44-p-ser516leu (accessed [today's date]).

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