Is AMDHD2 p.Glu157Lys (c.469G>A) pathogenic?

AMDHD2 p.Glu157Lys (c.469G>A) is classified Uncertain significance in AMDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.1304); Ultra-rare (popmax 0.0331%, mid).

How common is AMDHD2 p.Glu157Lys (c.469G>A) in the general population?

AMDHD2 p.Glu157Lys (c.469G>A) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about AMDHD2 p.Glu157Lys (c.469G>A)?

AlphaMissense predicts likely benign (score 0.1304) — an in-silico prediction, not a clinical call.

AMDHD2 p.Glu157Lys

c.469G>A · rs368676622 · VCV3115028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1304 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1304	likely benign
REVEL	0.617	indeterminate
SaProt	LLR -10.17	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,101 bp · p 0.046 · regional, not allelic
Overall
CADD	23.8	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 0.0331% Middle Eastern · 2/6,040 alleles

Filtering AF 0.0244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.0219% 349/1,594,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0403%	2,479
Middle Easterngrpmax	0.0331%	3,020
European (non-Finnish)	0.0269%	3,723
African / African-American	0.00401%	24,945
East Asian	0.00224%	44,740
Admixed American	0.00168%	59,650
South Asian	0.0011%	90,670

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu157Lys
Coding: c.469G>A
MANE Select: NM_001330449
dbSNP: rs368676622
Type: single nucleotide variant
Location: chr16:2527826 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49 · 2 PDB
Residue 157: an α-helix

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-glu157lys (accessed [today's date]).

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