Is PDCD1 p.Ala215Val (c.644C>T) pathogenic?

PDCD1 p.Ala215Val (c.644C>T) is classified Benign in PDCD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-24). AlphaMissense: likely benign (0.0889); Common (popmax 48%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about PDCD1 p.Ala215Val (c.644C>T)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

PDCD1 p.Ala215Val

Q: How common is PDCD1 p.Ala215Val (c.644C>T) in the general population?

PDCD1 p.Ala215Val (c.644C>T) is common (popmax 48%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.644C>T · rs2227982 · VCV1282693

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 48%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -6.74	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 0.61	GERP -1.1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,258 bp · p 0.14 · regional, not allelic
Overall
CADD	10.32	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 48% East Asian · 21,531/44,816 alleles

Filtering AF 47.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 47.3%

Overall 3.86% 62,111/1,610,454 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	48%	2
Admixed American	23.7%	4
South Asian	6.32%	16
Finnishnot grpmax-eligible	5.07%	20
Remaining individualsnot grpmax-eligible	4.47%	22
Ashkenazi Jewishnot grpmax-eligible	1.32%	76
European (non-Finnish)	1.14%	88
African / African-American	1.13%	88
Middle Eastern	0.697%	143

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: PDCD1
Protein: p.Ala215Val
Coding: c.644C>T
MANE Select: NM_005018
dbSNP: rs2227982
Type: single nucleotide variant
Location: chr2:241851281 (GRCh38)
Gene constraint: LOEUF 0.891 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 74.53 · 38 PDB
Residue 215: a UniProt-annotated variant site (in)

Full PDCD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDCD1 c.437-115G>A Benign ★★ same type
PDCD1 c.593-56C>G Benign ★★ same type
PDCD1 c.627+189G>A Benign ★★ same type
PDCD1 c.628-110A>G Benign ★★ same type
PDCD1 c.76+126G>C Benign ★★ same type
PDCD1 c.76+15C>T Benign ★★ same type
PDCD1 c.*889G>A Benign ★★ same type
PDCD1 p.Ala268= 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/pdcd1-p-ala215val (accessed [today's date]).

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