Is CARMIL2 p.Leu165Val (c.493C>G) pathogenic?

CARMIL2 p.Leu165Val (c.493C>G) is classified Uncertain significance in CARMIL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-23). AlphaMissense: ambiguous (0.4637); Ultra-rare (popmax 0.0495%, mid).

How common is CARMIL2 p.Leu165Val (c.493C>G) in the general population?

CARMIL2 p.Leu165Val (c.493C>G) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about CARMIL2 p.Leu165Val (c.493C>G)?

AlphaMissense predicts ambiguous (score 0.4637) — an in-silico prediction, not a clinical call.

CARMIL2 p.Leu165Val

c.493C>G · rs561206822 · VCV1352185

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4637 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4637	ambiguous
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.85, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,899 bp · p 0.31 · regional, not allelic
Overall
CADD	23.5	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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00223% 36/1,613,994 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0048%	20,827
East Asian	0.00446%	22,441
African / African-American	0.004%	25,019
Admixed American	0.00333%	30,017
European (non-Finnish)	0.00195%	51,299

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: CARMIL2
Protein: p.Leu165Val
Coding: c.493C>G
MANE Select: NM_001013838
dbSNP: rs561206822
Type: single nucleotide variant
Location: chr16:67646740 (GRCh38)
Gene constraint: LOEUF 0.701 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.50

Full CARMIL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARMIL2 c.1334+1G>T Likely pathogenic ★★ same type
CARMIL2 c.2313+1G>A Likely pathogenic ★★ same type
CARMIL2 c.871+1G>T Pathogenic ★★ same type
CARMIL2 c.958+1G>A Likely pathogenic ★★ same type
CARMIL2 p.Arg174Ter Pathogenic/Likely pathogenic ★★ same type
CARMIL2 p.Asn530Lys Pathogenic/Likely pathogenic ★★ same type
CARMIL2 p.Gln1379Ter Pathogenic/Likely pathogenic ★★ same type
CARMIL2 p.Ser370Ter Pathogenic ★★ 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/carmil2-p-leu165val (accessed [today's date]).

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