Is ANKAR p.Pro324Leu (c.971C>T) pathogenic?

ANKAR p.Pro324Leu (c.971C>T) is classified Uncertain significance in ANKAR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely pathogenic (0.6193); Ultra-rare (popmax 0.0162%, amr).

How common is ANKAR p.Pro324Leu (c.971C>T) in the general population?

ANKAR p.Pro324Leu (c.971C>T) is ultra-rare (popmax 0.0162%, amr) (gnomAD).

What do computational predictors say about ANKAR p.Pro324Leu (c.971C>T)?

AlphaMissense predicts likely pathogenic (score 0.6193) — an in-silico prediction, not a clinical call.

ANKAR p.Pro324Leu

c.971C>T · VCV3541511

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6193 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0162%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6193	likely pathogenic
REVEL	0.251	benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 70 kb · p 0.0059 · regional, not allelic
Overall
CADD	25.6	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 0.0162% Admixed American · 8/49,454 alleles

Filtering AF 0.00803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0058%

Overall 0.00349% 55/1,573,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0691%	1,448
Admixed Americangrpmax	0.0162%	6,182
Remaining individualsnot grpmax-eligible	0.0099%	10,103
African / African-American	0.00275%	36,357
European (non-Finnish)	0.00171%	58,346

Ashkenazi Jewish 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: ANKAR
Protein: p.Pro324Leu
Coding: c.971C>T
MANE Select: NM_001378068
Type: single nucleotide variant
Location: chr2:189689896 (GRCh38)
Gene constraint: LOEUF 1.07 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.79

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

Similar variants

OSGEPL1 p.Ser324Ala Uncertain significance ★ ⚠ same residue
ANKAR p.Asn938= Benign ★★ same type
ANKAR p.Gln1419Leu Benign ★★ same type
ANKAR p.Ile1349= Benign ★★ same type
ANKAR p.Leu94Arg Benign ★★ same type
ANKAR p.Thr206Ala Benign ★★ same type
ANKAR p.Thr92= Benign ★★ same type
ANKAR p.Tyr1262Ser 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/ankar-p-pro324leu (accessed [today's date]).

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