Is CTCFL p.Ala438Thr (c.1312G>A) pathogenic?

CTCFL p.Ala438Thr (c.1312G>A) is classified Uncertain significance in CTCFL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: ambiguous (0.4427); Ultra-rare (popmax 0.0198%, sas).

How common is CTCFL p.Ala438Thr (c.1312G>A) in the general population?

CTCFL p.Ala438Thr (c.1312G>A) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about CTCFL p.Ala438Thr (c.1312G>A)?

AlphaMissense predicts ambiguous (score 0.4427) — an in-silico prediction, not a clinical call.

CTCFL p.Ala438Thr

c.1312G>A · VCV3837100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4427 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4427	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -5.51	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 0.36	GERP 0.51, phastCons 0.021
Regional constraint	o/e 0.76	unconstrained · MANE · 11 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	23.0	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 0.0198% South Asian · 18/91,064 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00223% 36/1,614,102 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,059
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.00136%	73,750
African / African-American	0.00133%	75,024

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: CTCFL
Protein: p.Ala438Thr
Coding: c.1312G>A
MANE Select: NM_001386993
Type: single nucleotide variant
Location: chr20:57514610 (GRCh38)
Gene constraint: LOEUF 0.669 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.75

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

Similar variants

CTCFL p.Ser172= Benign ★★ same type
CTCFL p.Val652Met Benign ★★ same type
CTCFL p.Ala155Ser Uncertain significance ★ ⚠ same type
CTCFL p.Ala155Thr Uncertain significance ★ ⚠ same type
CTCFL p.Ala253Thr Uncertain significance ★ ⚠ same type
CTCFL p.Ala321Thr Uncertain significance ★ ⚠ same type
CTCFL p.Ala434Thr Uncertain significance ★ ⚠ same type
CTCFL p.Ala494Val 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/ctcfl-p-ala438thr (accessed [today's date]).

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