Is AMDHD2 p.Arg11Cys (c.31C>T) pathogenic?

AMDHD2 p.Arg11Cys (c.31C>T) is classified Uncertain significance in AMDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.2224); Very rare (popmax 0.00323%, eas).

How common is AMDHD2 p.Arg11Cys (c.31C>T) in the general population?

AMDHD2 p.Arg11Cys (c.31C>T) is very rare (popmax 0.00323%, eas) (gnomAD).

What do computational predictors say about AMDHD2 p.Arg11Cys (c.31C>T)?

AlphaMissense predicts likely benign (score 0.2224) — an in-silico prediction, not a clinical call.

AMDHD2 p.Arg11Cys

c.31C>T · rs761700526 · VCV2616463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00323%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2224	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -10.52	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1.1, phastCons 0.084
Regional constraint	o/e 0.92	unconstrained · MANE · 9,101 bp · p 0.046 · regional, not allelic
Overall
CADD	18.26	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 0.00323% East Asian · 1/30,990 alleles

Filtering AF 0.000351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000254%

Overall 0.000834% 9/1,078,912 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00323%	30,990
European (non-Finnish)	0.000816%	122,523

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: AMDHD2
Protein: p.Arg11Cys
Coding: c.31C>T
MANE Select: NM_001330449
dbSNP: rs761700526
Type: single nucleotide variant
Location: chr16:2520489 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49 · 2 PDB

Full AMDHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATP6V0C p.Pro49Leu Likely pathogenic ★★ same type
ATP6V0C p.Ala95Thr Likely pathogenic ★ same type
AMDHD2 c.970+10C>T Uncertain significance ★ same type
AMDHD2 c.970+19T>G Uncertain significance ★ same type
AMDHD2 c.970+40C>T Uncertain significance ★ same type
AMDHD2 c.970+7G>A Uncertain significance ★ same type
AMDHD2 c.971-18G>A Uncertain significance ★ same type
AMDHD2 c.971-27C>G 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/amdhd2-p-arg11cys (accessed [today's date]).

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